Chronic pain, including chronic orofacial pain, remains unsuccessfully treated in a large number of patients. Furthermore, the loss of analgesic efficacy with chronic administration of frontline analgesic drugs, such as morphine, severely limits their use. Recent data strongly suggest that spinal cord glia (astrocytes and microglia) oppose the analgesic effects of morphine, through the release of proinflammatory cytokines: tumor necrosis factor (TNF), interleukin-1 (IL1) &interleukin-6 (IL6). While as yet unexplored, this raises the possibility that glial activation by clinically relevant opioid analgesics may be broad in scope, rather than a phenomenon restricted to morphine. Therefore, (a) clinical pain control may currently be hindered by opioid-induced glial activation &, (b) if this is true, clinical pain control could be improved by finding ways to prevent or circumvent the effects of glial activation by opioid analgesics. Therefore, the aims of the proposal are to determine whether: (I) clinically relevant opioid analgesics, in general, induce proinflammatory cytokines in trigeminal nuclei, and also in spinal cord under normal (sham) &/or neuropathic (chronic constriction injury;CCI) pain conditions. Further, whether an anti-inflammatory cytokine will "unmask" analgesia following chronic opioid administration. The potential for chronically enhancing analgesic efficacy by chronic co-administration of an anti-inflammatory cytokine will also be explored. (II) the induction of spinal proinflammatory cytokines by morphine &other opioids is mediated, in part, via actions of their common, active metabolites (M6G or M3G);and (III) the elevated production/release of trigeminal and spinal proinflammatory cytokines induced by opioid pharmacotherapies is mediated via classical opioid receptors. Moreover, whether selective mu, delta &kappa receptor agonists mimic the effects of clinically relevant analgesics. Where feasible, sciatic CCI will be replaced by CCI of the infraorbital nerve &assessment of orofacial mechanical allodynia &thermal hyperalgesia. Together these studies will provide novel insights into the actions of opioid analgesics at both trigeminal &spinal sites, &will explore the potential for using anti-inflammatory cytokines as a means of potentiating the magnitude &duration of analgesia to relieve normal &neuropathic pain. If successful, these studies will lead to development of novel adjunct therapies for improving clinical pain control by controlling the negative consequences of opioid-induced glial activation.